Crystal Associated Renal Inflammation and Treatment Options

点击翻译按钮获取中文摘要

DESCRIPTION (provided by applicant): Crystals of calcium oxalate (CaOx), are major constituents of most urinary stones. They are also seen deposited in the kidneys of patients with primary or enteric hyperoxaluria. These crystals can be nephrotoxic, evoke an inflammatory response leading to fibrosis, loss of nephrons and possible renal failure. Tissue culture studies indicate that interactions between the crystals and renal cells produce reactive oxygen species (ROS), which appear to mediate many of the cellular responses. CaOx crystal deposition in rat kidneys leads to oxidant stress, is associated with the activation of renin-angiotensin system (RAS), and increases in the production of macromolecules such as osteopontin (OPN) that modulate crystal formation and their retention within the kidneys. Interstitial CaOx Crystal deposits are surrounded by monocytes and macrophages. Exposure of renal epithelial cells in culture to CaOx and CaP crystals is associated with increased production of the chemokine, monocyte chemoattractant protein-1 (MCP-1). Treatments with anti-oxidants, free radical scavengers, or angiotensin receptor blockers reduce CaOx crystal deposition in the kidneys of experimental animals. Based on these results, we hypothesize that "Renal crystal deposition induces inflammation in kidneys via the activation of renin-angiotensin system and NADPH oxidase, and production of reactive oxygen species. Reduction in ROS production will reduce the synthesis of macromolecules such as OPN and MCP-1 thereby reducing migration of monocytes and macrophages into the renal interstitium and subsequent inflammation and fibrosis." We propose to rigorously test this hypothesis in vivo using a rat model of renal CaOx crystal deposition and in vitro by exposing NRK52E and MDCK cells in culture to CaOx crystals, in order to define the precise series of molecular events that link intrarenal crystal deposition and eventual fibrosis. Results of such studies will improve the understanding of CaOx induced inflammation in nephrocalcinosis and nephrolithiasis. Studies may provide novel treatment targets and better treatment options to prevent the renal scarring that is associated with primary and enteric hyperoxaluria. PUBLIC HEALTH RELEVANCE: Calcium oxalate crystal deposition in the kidneys is common in patients with primary and enteric hyperoxaluria, causing renal injury and inflammation. Enteric hyperoxaluria secondary to bariatric surgery is a serious emerging health problem. We are proposing to study the series of molecular events that link intrarenal crystal deposition and eventual fibrosis by exposing NRK52E and MDCK cells in culture to CaOx crystals and using a rat model of renal CaOx crystal deposition. Results of such studies will improve the understanding of CaOx induced inflammation and provide novel treatment targets and better treatment options to prevent the renal scarring that is associated with primary and enteric hyperoxaluria.